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Lung cancer is the leading cause of cancer-related deaths worldwide. ALK receptor tyrosine kinase gene (ALK) rearrangement has been identified in 3% to 5% of patients with NSCLC. The most common ALK rearrangement is echinoderm microtubule associated protein like 4 (EML4)-ALK, with several variants that can be targeted by the tyrosine kinase inhibitor crizotinib.In this study using comprehensive next-generation sequencing targeting 416 pan-cancer genes and introns of 16 genes frequently rearranged in cancer, we identified a novel cut-like homeobox 1 gene (CUX1)-ALK fusion gene in a patient with lung adenocarcinoma. The exact CUX1-ALK fusion transcript was determined by RNA sequencing and confirmed by reverse-transcriptase polymerase chain reaction. The oncogenic ability of CUX1-ALK fusion gene was further validated in cells of the line 293T for the activation of anaplastic lymphoma kinase (ALK) self-phosphorylation and downstream signaling pathways.After detection of the CUX1-ALK fusion gene, RNA sequencing analysis of formalin-fixed paraffin-embedded sections from the primary tumor specimen was applied to reveal a 97-nucleotide fragment from CUX1 intron 8 inserted before the nucleotide 53 position in ALK exon 20. Expression of the cut-like homeobox 1–ALK fusion protein in 293T cells confirmed the self-phosphorylation of the fusion protein and the activation of ALK downstream signaling pathways, including the mitogen-activated protein kinase, Janus kinase–signal transducer and activator of transcription, and phosphoinositide 3-kinase/AKT signaling pathways, which could all be inhibited by the addition of crizotinib. Furthermore, the patient showed a superior response to crizotinib, with a progression-free survival of 20 months.This study provides the novel finding of a CUX1-ALK fusion gene from a patient with NSCLC that could provide personalized treatment solutions for the maximum benefit to patients with NSCLC.